Citations

Abstract Many cancer researchers are currently generating heterogeneous genomic data sets containing mRNA expression, array based comparative genomic hybridization (aCGH), and other information from multiple patients. In the near future, data sets will likely include proteomics, methylomics, and high throughput sequencing data. Analytical tools that integrate these different data types to prioritize genes for further study have lagged, however. With this in mind, we have implemented a standalone software application that integrates CGH and mRNA expression profiling data. This application implements several different methods to generate ranked lists of genes and genomic regions based on breakpoint frequency, aberration frequency, and the impact of copy number changes on mRNA expression. The software is Java GUI based, with abstracted object models that can be extended as new genomic data types and annotations become available. We used this application to analyze aCGH datasets generated from 22 primary pancreatic tumor xenografts and mRNA expression datasets from 16 of the 22 samples. Genes which were located near a putative breakpoint and whose expression levels were high in a majority of the xenografts samples were considered putative targets. Preliminary IHC analysis of pancreas primary tumor tissue microarrays confirms one of these putative targets, Chemokine (CXC motif) Ligand 5 (CXCL5). By allowing cancer researchers to correlate genomic aberrations with expression data, we believe that this application will generate more meaningful targets for further biomarker identification and/or drug target discovery. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A30.

Osteoporosis and age-related bone loss are important public health concerns. Therefore, there is a high level of interest in the development of medical interventions and lifestyle changes that reduce the incidence of osteoporosis and age-related bone loss. Decreased bone mineral density is associated with high cholesterol, and patients on statins have increased bone mineral densities, strongly implicating cholesterol as a negative regulator of bone homeostasis. In this study, using both molecular and pharmacological approaches, we have been able to demonstrate that the primary cholesterol metabolite, 27-hydroxycholesterol, through its actions on both estrogen receptors and liver X receptors, decreases osteoblast differentiation and enhances osteoclastogenesis, resulting in increased bone resorbtion in mice. Induction of the short heterodimer partner protein by estrogens in osteoblasts can attenuate the liver X receptor-mediated actions of 27-hydroxycholesterol in bone. These data establish a mechanistic link between cholesterol and bone quality, highlight an unexpected target of estrogens in osteoblasts, and define a signaling axis, the therapeutic exploitation of which is likely to yield novel antiosteoporotic drugs.

OBJECTIVE In patients with type 2 diabetes, glucagon levels are often increased. Furthermore, pulsatile secretion of insulin is disturbed in such patients. Whether pulsatile glucagon secretion is altered in type 2 diabetes is not known. RESEARCH DESIGN AND METHODS Twelve patients with type 2 diabetes and 13 nondiabetic individuals were examined in the fasting state and after mixed meal ingestion. Deconvolution analyses were performed on insulin and glucagon concentration time series sampled at 1-min intervals. RESULTS Both insulin and glucagon were secreted in distinct pulses, occurring at ∼5-min intervals. In patients with diabetes, postprandial insulin pulse mass was reduced by 74% (P < 0.001). Glucagon concentrations were increased in the patients during fasting and after meal ingestion (P < 0.05), specifically through an increased glucagon pulse mass (P < 0.01). In healthy subjects, the increase in postprandial insulin levels was inversely related to respective glucagon levels (P < 0.05). This relationship was absent in the fasting state and in patients with diabetes. CONCLUSIONS Glucagon and insulin are secreted in a coordinated, pulsatile manner. A plausible model is that the postprandial increase in insulin burst mass represses the corresponding glucagon pulses. Disruption of the insulin–glucagon interaction in patients with type 2 diabetes could potentially contribute to hyperglucagonemia.

Abstract Whether hemoglobin A1c (HbA1c) values are suitable for diagnosing diabetes has been debated. We sought to assess the prevalence of elevated HbA1c levels in a prediabetes patient population. Oral glucose tolerance tests and HbA1c levels were analyzed for patients entering a diabetes prevention program between January 1, 2007, and September 13, 2009. We calculated the percentage of patients with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) who had HbA1c values in the 6.0% to 6.4% range or in the 5.7% to 6.4% range. The mean age of the 242 patients was 62 years; 64.0% were women, and 88.0% were white. Isolated IFG was detected in about 56.2% of patients and combined IFG and IGT in about 37.2%. Only 28.5% of patients had HbA1c values in the 6.0% to 6.4% range, whereas 65.3% had values in the 5.7% to 6.4% range. Our data suggest that reliance on HbA1c testing alone to identify candidates for a diabetes prevention program would miss a substantial number of eligible patients.

Background— Data regarding the familial aggregation of left ventricular (LV) geometry and its relations to parental heart failure (HF) are limited. Methods and Results— We evaluated concordance of LV geometry within 1093 nuclear families in 5758 participants of the original (parents) (n=2351) and offspring (n=3407) cohorts of the Framingham Heart Study undergoing routine echocardiography in mid- to late adulthood. LV geometry was categorized based on cohort- and sex-specific 80th percentile cutoffs of LV mass and relative wall thickness (RWT) into normal (both <80th percentile), concentric remodeling (LV mass <80th percentile; RWT >80th percentile), concentric hypertrophy (both >80th percentile), and eccentric hypertrophy (LV mass >80th percentile; RWT <80th percentile). Within nuclear families, LV geometry was concordant among related pairs (parent-child, sibling-sibling) ( P =0.0015) but not among unrelated spousal pairs ( P =0.60), a finding that remained unchanged after adjusting for clinical covariates known to influence LV remodeling (age, systolic blood pressure, body mass index), excluding individuals with prevalent HF and myocardial infarction, and varying the thresholds for defining LV geometry. The prevalence of abnormal LV geometry was higher in family members of affected individuals, with recurrence risks of 1.4 for concentric remodeling (95% CI, 1.2 to 1.7) and eccentric hypertrophy (95% CI, 1.1 to 1.8) and 3.9 (95% CI, 3.2 to 4.6) for concentric hypertrophy. In a subset of 1497 offspring, we observed an association between parental HF (n=458) and eccentric hypertrophy in offspring ( P <0.0001). Conclusions— Our investigation of a 2-generational community-based sample demonstrates familial aggregation of LV geometry, with the greatest recurrence risk for concentric LV geometry, and establishes an association between eccentric LV geometry and parental HF.